LA JOLLA, Calif.—Recent research out of the Sanford-Burnham
Medical Research Institute provides important clues about the molecular
mechanisms underlying the development and progression of melanoma—the deadliest
form of skin cancer—and how these mechanisms allow melanoma to resist therapy.

In a study published Feb. in the Elsevier journal Cell, the Sanford-Burnham team
demonstrates how the transcription factor ATF2, which is associated with poor
prognosis in melanoma, elicits oncogenic activities in melanoma and tumor
suppressor activities in nonmalignant skin cancer. Led by Dr. Ze'ev Ronai, the
senior author of the study, the researchers identified that the ATF2 tumor
suppressor function is determined by its ability to localize at the
mitochondria, where it alters membrane permeability following genotoxic stress.

Ronai's laboratory at Sanford-Burnham is directed toward
understanding the regulation and function of the signaling pathways that play a
central role in the mammalian stress response. In particular, it is focused on
ubiquitin ligases and protein kinases that cooperate in the regulation of
important cellular functions, including hypoxia, ER stress and the cell cycle.

"We have been working on skin cancer in its non-malignant
forms for the last 20 years. In the course of these studies, we have made some
important discoveries," says Ronai, who is associate director of
Sanford-Burnham's NCI-designated Cancer Center. "In the last few years, we have
made enormous progress in the area of melanoma to the degree that we now have
specific drugs that can target forms of the tumor. Despite this progress, we
now realize that we need to overcome the challenge of resistance that emerge in
most cases—and there is a tremendous effort being placed on how to overcome
this as we speak."

This resistance, known as oncogene addiction—which has been
called the "Achilles' heel of cancer"—is defined as a condition in which
disruption of one gene or protein leads to the death of the cancer cell. Many
cancer research teams are working to exploit this phenomenon therapeutically by
"switching off" the pathway upon which cancer cells have become dependent in an
effort to destroy the cancer cell while sparing normal, healthy cells from
damage.

ATF2 is a "two-faced" protein—in melanoma cells, it's
oncogenic, or cancer-causing, while in non-malignant types of skin cancers, it
acts as a tumor suppressor. Ronai's team identified a molecular switch called
protein kinase Cɛ
(PKCɛ) that
controls ATF2's dual functions. PKCɛ disables ATF2's tumor-suppressing activities, sensitizing
cells to chemotherapy and enhancing ATF2's tumor-promoting activity. The team
also found that high levels of PKCɛ in melanoma are associated with poor prognosis.

"PKCɛ is the culprit behind melanoma's oncogenic addiction,"
explains Ronai. "ATF2 is normally a 'good guy.' But when there is too much PKCɛ—as in malignant
melanoma—ATF2 becomes an oncogene, promoting tumor development."

In this study, Ronai and his colleagues found that PKCɛ's malignant
power is in its ability to direct ATF2's location and activity within a cell.
In a normal cell, PKCɛ
modifies ATF2, keeping it in the nucleus, where it turns genes on and off and
helps repair damaged DNA. When the cell experiences exposure to toxicity or
stress, PKCɛ
backs off and ATF2 is able to move out of the nucleus and to the mitochondria,
the part of the cell that generates energy and helps control cellular life and
death. When it gets there, ATF2 helps to set the cell on a death course—a
safeguard cells use to prevent errors that often make them cancerous.

PKCɛ levels are abnormally high in melanoma, and more PKCɛ means more ATF2
stuck in the nucleus, where it can't help the cells to die. Instead, in the
nucleus, ATF2 promotes cellular survival and thus contributes to tumor
development the researchers found.

Ronai's laboratory is now searching for small molecules that
help release ATF2 from PKCɛ's grip, thus resuming ATF2's ability to promote cell death
when needed. Since such an approach will effectively kill melanoma cells, it is
expected to offer new therapeutic options for melanoma, and possibly other
tumors with high PKCɛ
levels.

"The development of a treatment for melanoma is moving at a
tremendous pace," says Ronai. "There is great knowledge being added as we
speak. I believe that by sequencing tumors from melanomas, highlighting new
mutations and offering potential targets by specific immunotherapeutics, we
will have a treatment for melanoma in the next two to three years. I believe we
will be able to move forward in recognizing that there is no one magic drug,
but a combination of drugs based on our knowledge of changes in different
signaling pathways."

The study, "PKCε Promotes Oncogenic Functions of ATF2 in the
Nucleus while Blocking Its Apoptotic Function at Mitochondria," was funded by
the National Cancer Institute and the American Cancer Society, Illinois
Division. Ronai's co-authors included Eric Lau, Sanford-Burnham; Harriet Luger,
Yale University; Tal Varsano, Sanford-Burnham; KiYoung Lee, University of
California, San Diego and Ajou University; Immo Scheffler, University of
California, San Diego; David Rimm, Yale University; and Trey Ideker, University
of California, San Diego.